1. Field of the Invention
The present invention relates to antidotes for blood agents. More particularly, the invention relates to cyanide antidotes.
2. Brief Description of the Related Art
Cyanide (CN) intoxication in humans can occur in a number of scenarios including as part of a chemical weapon-based military conflict. CN causes rapid and extensive cellular hypoxia through the binding of the ferric (Fe3+) iron in the cytochrome c oxidase system leading to the collapse of the electron transport chain and thereby inhibiting the efficiency of oxygen transport to the tissues. Common cyanide compounds include hydrogen cyanide gas, cyanogen chloride gas, and crystalline solids such as potassium cyanide and sodium cyanide. The ease of delivery of these agents (especially gaseous cyanides) allow them to be used as an attack agent in chemical warfare.
Therapeutic attempts to counteract cyanide poisoning have been developed to inhibit the toxic effects of cyanide. For example, oxygen, sodium thiosulfate, amyl nitrite, sodium nitrite, 4-dimethylaminophenol, hydroxocobalamin, dicobalt EDTA, garlic extracts, disulfides, sodium pyruvate, alpha-keto-glutaric acid, aqueous solutions of ferrous sulfate in a citric acid sodium carbonate solution have been used for cyanide detoxification.
Presently in the United States two kits have been accepted as the standard of care. One is based on the intravenous administration of a combination of sodium nitrite and sodium thiosulfate (TS) (Nithiodote®), while the other intravenously used preparation contains hydroxocobalamin (Cyanokit®). Hydroxocobalamin binds to CN and forms cyanocobalamin, which is then excreted in the urine. Sodium nitrite leads to the formation of methemoglobin which has high affinity to CN and forms a relative stable complex of cyanomethemoglobin. Acting as a sulfur donor, TS helps bolster the natural CN detoxification by endogenous sulfur transferases, such as rhodanese (Rh), which utilize sulfur and convert CN into thiocyanate.
U.S. Pat. No. 4,565,311 to Samoff, which is incorporated herein by reference, describes as an antidote for cyanide poisoning injectable hydroxylamine hydrochloride. This is followed by treatment with thiosulfate. The hydroxylamine hydrochloride can also be employed as a respiratory stimulant in treating other illnesses.
Zottola et al. in “Disulfides as Cyanide Antidotes: Evidence for a New In Vivo Oxidative Pathway for Cyanide Detoxification.” Chemical Research Toxicology, 2009, 22, pp. 1948-1953, which is incorporated herein by reference, describes the conversion of cyanide to thiocyanate (SCN) in the presence of the enzyme rhodanese. Rhodanese is an enzyme found primarily in the mitochondria. In a mammal, rhodanese is thought to be primarily responsible for the conversion of cyanide to SCN. Thiocyanate is then excreted by the kidney. Oxidized sulfur species such as sodium thiosulfate have been shown to be effective in vitro donors for rhodanese, however sodium thiosulfate in vivo efficacy is highly limited due to its limited cell penetration capability to reach the endogenous rhodanese. Thus, more effective sulfur analogs are desired.
The present therapies of sodium thiosulfate (TS) and sodium nitrite (SN) (Nithiodote®), and the hydroxocobalamin (Cyanokit®) both have limitations of requiring intravenous administration. Additionally, TS is highly dependent on the presence of sulfurtransferase enzyme (Rhodanese), and cannot easily penetrate through the mitochondrial membrane to reach the endogenous Rhodanese. The Cyanokit® requires high volume of administration to reach the required dose. There is, therefore, a need to develop a new, fast acting cyanide antidote that can be administered in a way that provides rapid absorption to protect individuals without requiring specialized techniques such as intravenous injection.